Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCA047

Poster Communications

The cardiovascular role of uncoupling protein 2 (Ucp2): Is it cardiac-specific and an uncoupling protein?

H. Kutsche1, C. Hirschhäuser1, R. Schreckenberg1, M. Weber1, R. Schulz1, K. Schlueter1

1. Dept. of Physiology, Justus-Liebig-University, Giessen, Germany.


Uncpoupling protein 1 (ucp1), also known as thermogenin, is an uncoupling protein in the brown fat tissue. Two other ucp isoforms, named ucp2 and ucp3, seemed to play distinct roles in various tissues including the heart although a relative high homology among ucp family members suggests a similar function. Upregulation of ucp2 in hypertrophic hearts may indicate a role for ucp2 this protein in this process, but the potential mechanism remains unclear. We performed experiments with adult ventricular cardiomyocytes from mice and rats (AMVC and ARVC) to study the role of ucp2 during hypertrophy and transition to heart failure. In ARVC, silencing of ucp2 significantly increased a process known as "cell spreading" that is required for cellular adaptation to stress conditions (15±7% vs. 27±6% of all cells). Furthermore, silencing of ucp2 by siRNA directed against the molecule as well as genipin, a pharmacological inhibitor of ucps, attenuated an angiotensin II (Ang-II)-dependent loss of load free cell shortening (%-cell shortening: 6.11±2.85 vs. 9.52±2.56; 6.39±2.82 vs. 8.34±2.54; n=120 cells; 15 culture dishes; 3 preparations). These experiments suggest that ucp2 participates in the transition of adaptive hypertrophy to maladaptive hypertrophy. It has been suggested that ucp2 reduces oxidative stress in mitochondria. However, neither pharmacological inhibition nor genetic depletion (ucp2-/- mice) affected ROS formation of isolated mitochondria. On the other hand, silencing of ucp2 increased the amount of glucose transport proteins, such as Glut-4 and Glut-12 (x-fold: 1.31±0.18 and 1.42±0.32). Furthermore, silencing of ucp2 reduced the concentration of intracellular lactate indicating an improvement of oxidative phosphorylation with glucose as the dominant substrate (by 31%). In ARVC ucp2 is the main isoform of the ucps. Silencing of ucp2 significantly improved the cell function upon exposure to Ang-II, improved cellular adaptation (spreading) und reduced glycolysis. In contrast, in AMVC ucp2 and ucp3 are equally expressed but silencing of ucp2 did not improve Ang-II-dependent functional loss. Nevertheless, ucp2 mice show increased Glut expression and improved function upon hypertrophic stimuli such as pulmonary artery banding (PAB). In conclusion, animals benefit from low ucp2 expression by upregulation of glucose transporters and promotion of oxidative phosphorylation.

Where applicable, experiments conform with Society ethical requirements